Acylation isocyanoacetic acid ester

Shiori and co-workers used 5-substituted 4-oxazolecarboxylic acid esters 379 as p-hydroxy-a-amino acid synthons. They described a straightforward synthesis of 379 by acylation of an isocyanoacetic acid ester with an a-alkoxyacid 378 in the presence of diphenylphosphorylazide (DPPA) or diethylphosphoryl cyanide (DPPC) followed by base-catalyzed cyclization (Scheme 1.104). The reaction conditions do not epimerize optically active a-alkoxyacids. Dilute acid hydrolysis of 379 and reaction with (600)2 affords the protected aminotetronic acids 380. Stereoselective hydrogenation of 380 then yields the 1,4-lactones 381, key intermediates in the synthesis of amino sugars. A variety of a-alkoxyacids were studied, and some examples are shown in Table 1.30. 

Several other methods for the synthesis of N-acyl A -amino acid derivatives have been described. These include the condensation of aldehydes or ketones with isocyanoacetates followed by transformation of the resultant iV-formyl derivatives, 7V-chlorination of A -acyl amino acid esters followed by elimination of HCl using DBU, reaction of a-oxo carboxylic acids with amides or methyl carbamates and enzymatic dehydrogenation of A -acyl amino acid amides ". With the exception of the last, these methods have not been reported so far in isotope chemistry. 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

Ozaki and co-workers prepared an extensive series of 5-aryl(heteroaryl)-4-oxazolecarboxylic acid methyl esters 368 (20 compounds) from acylation of methyl isocyanoacetate, followed by in situ cyclization (Scheme 1.100). These compounds were elaborated further and evaluated as blood platelet aggregation inhibitors. 

Hydroxy-a-amino-acids are available by reduction and hydrolysis of the corresponding jS-keto-esters, obtained from methyl isocyanoacetate and acyl halides via oxazole-4-carboxylate intermediates. ° A synthesis of L-y-amino-/3-hydroxybutyric acid has been reported in which the key step is a dehydration of L-a-hydroxysuccinamic acid to the corresponding y-cyano-acid, presumably via a y-iminobutyrolactone. ° This could prove to be a general route to (3- and y-cyano-carboxylic acids. 

DPPA has been used for the direct C-acylation of methyl isocyanoacetate with carboxylic acids to give 4-methoxycarbonyloxazoles. t-Daunosamine, the glycone component of anticancer anthracycline antibiotics, has been synthesized from L-lactic acid in 9 steps with a 24% overall yield, where a key step in the sequence is the direct C-acylation of methyl isocyanoacetate with the lithium salt of the lactate ester using diphenyl phosphorazidate (eq 7). 

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